Lysosomal storage disorders represent a group of over 40 distinct genetic diseases and are caused by abnormalities of enzymes present in lysosomes. Individuals that are affected with a lysosomal storage disorder present a wide range of clinical symptoms depending upon the specific disorder and the particular genotype involved. The clinical symptoms associated with lysosomal storage disorders can have a devastating impact on affected individuals and their families. For example, reticuloendothelial disease, central nervous system dysfunction, behavioral problems, and severe mental retardation are characteristic of many lysosomal storage disorders. In a specific lysosomal storage disorder group called mucopolysaccharidoses (MPS), other clinical symptoms may include skeletal abnormalities, organomegaly, corneal clouding, and dysmorphic features.
The mucopolysaccharidoses (MPS) are a group of 11 distinct enzyme deficiencies that result in defective catabolism of glycosaminoglycans (GAGs). Neufeld et al., “The Mucopolysaccharidoses,” In: METABOLIC AND MOLECULAR BASIS OF INHERITED DISEASE 3421-3452 (Scriver et al., eds McGraw-Hill) (2001). Due to these inherited enzyme defects, glycosaminoglycans (GAGs) progressively accumulate in lysosomes and other intracellular compartments of MPS patients, as well as in extracellular connective tissue matrices. As expected, the major clinical consequences of these enzyme deficiencies are most evident in connective tissue organs, including cartilage, skin, and bone. Major clinical features include a coarse and abnormal facial appearance and cranial development, short limbs, degenerative joint disease, trachea and heart valve defects, and in some cases neurological involvement. Patients are usually born without visible clinical features of MPS, but can develop progressive clinical involvement. In severe cases, an affected child may require constant medical management but still often die before adolescence.
Another type of lysosomal storage disorder, Niemann-Pick disease, also known as sphingomyelin lipidosis, comprises a group of disorders characterized by foam cell infiltration of the reticuloendothelial system. Foam cells in Niemann-Pick become engorged with sphingomyelin and, to a lesser extent, other membrane lipids including cholesterol. Niemann-Pick is caused by inactivation of the enzyme acid sphingomyelinase in Types A and B disease, with more residual enzyme activity in Type B (see Kolodny et al., “Storage Diseases of the Reticuloendothelial System,” in NATHAN AND OSKI'S HEMATOLOGY OF INFANCY AND CHILDHOOD 5th ed., vol. 2, 1461-1507 (David G. Nathan and Stuart H. Orkin, Eds., W.B. Saunders Co.) (1998)). The pathophysiology of major organ systems in Niemann-Pick can be briefly summarized as follows. The spleen is the most extensively involved organ of Type A and B patients. The lungs are involved to a variable extent, and lung pathology in Type B patients is the major cause of mortality due to chronic bronchopneumonia. Liver involvement is variable, but severely affected patients may have life-threatening cirrhosis, portal hypertension, and ascites. The involvement of the lymph nodes is variable depending on the severity of disease. Central nervous system involvement differentiates the major types of Niemann-Pick. While most Type B patients do not experience central nervous system involvement, it is characteristic in Type A patients. The kidneys are moderately involved in Niemann Pick disease.
Several approaches have been evaluated for the treatment of these lysosomal storage disorders, including bone marrow transplantation and enzyme replacement therapy. Bone marrow transplantation has proven effective to varying degrees, but, when administered alone, has limited effects on the bones and joints. Clarke, L A, “The Mucopolysaccharidoses: A Success of Molecular Medicine,” Expert Rev. Mol. Med. 10:e1 (2008). It also is impeded by the deleterious side effects of immunosuppressive and myeloablative medications, and the occurrence of graft versus host disease. The use of cord blood has partially mitigated these complicating factors, although they often remain significant. Enzyme replacement therapy involves the intravenous infusion of recombinant enzymes, usually weekly or biweekly. Clarke, L A, “The Mucopolysaccharidoses: A Success of Molecular Medicine,” Expert Rev. Mol. Med. 10:e1 (2008). In large part, the effectiveness of enzyme replacement therapy relies on the biodistribution of the infused enzymes, which are readily delivered to the reticuloendothelial organs (e.g., liver, spleen), but less so to other organs. For the MPS disorders, enzyme replacement therapy is available for three types: MPS I (Hurler/Schie Syndrome) (Wraith et al., “Mucopolysaccharidosis Type II (Hunter Syndrome): A Clinical Review and Recommendations For Treatment in the Era of Enzyme Replacement Therapy,” Eur. J. Pediatr. 167:267-77 (2008); Cox-Brinkman et al., “Ultrastructural Analysis of Dermal Fibroblasts in Mucopolysaccharidosis Type I: Effects of Enzyme Replacement Therapy and Hematopoietic Cell Transplantation,” Ultrastruct. Pathol. 34:126-32 (2010); Coppa et al., “Effect of 6 Years of Enzyme Replacement Therapy on Plasma and Urine Glycosaminoglycans in Attenuated MPS I Patients,” Glycobiology 20:1259-73 (2010)); MPS II (Hunter Syndrome) (Glamuzina et al., “Treatment of Mucopolysaccharidosis Type II (Hunter Syndrome) With Idursulfase: The Relevance of Clinical Trial End Points,” J. Inherit. Metab. Dis. (2011)); and MPS VI (Maroteaux-Lamy Syndrome) (Decker et al., “Enzyme Replacement Therapy for Mucopolysaccharidosis VI: Growth and Pubertal Development in Patients Treated With Recombinant Human N-Acetylgalactosamine 4-Sulfatase,” J. Pediatr. Rehabil. Med. 3:89-100 (2010); Valayannopoulos et al., “Mucopolysaccharidosis VI Orphanet,” J. Rare Dis. 12:5 (2010); McGill et al., “Enzyme Replacement Therapy for Mucopolysaccharidosis VI From 8 Weeks of Age—A Sibling Control Study,” Clin. Genet. 77:492-498 (2010)). Significant quality-of-life improvements have been noted following enzyme replacement therapy, including improved mobility, breathing, and joint flexibility. However, there is little or no evidence that enzyme replacement therapy directly impacts the cartilage and bone disease in MPS patients, and these positive clinical effects are therefore thought to derive mostly from soft tissue changes (e.g., tendons). Other experimental therapies are also under evaluation for the MPS disorders, including gene therapies (Cotugno et al., “Different Serum Enzyme Levels are Required to Rescue the Various Systemic Features of the Mucopolysaccharidoses,” Hum. Gene Ther. 21:555-69 (2010); Herati et al., “Radiographic Evaluation of Bones and Joints in Mucopolysaccharidosis I and VII Dogs After Neonatal Gene Therapy,” Mol. Genet. Metab. 95:142-51 (2008)) and the use of recombinant enzymes fused to cell-specific targeting sequences (Lu et al., “Expression in CHO Cells and Pharmacokinetics and Brain Uptake in the Rhesus Monkey of an IgG-Iduronate-2-Sulfatase Fusion Protein,” Biotechnol. Bioeng. (2011); Osborn et al., “Minicircle DNA-Based Gene Therapy Coupled With Immune Modulation Permits Long-term Expression of α-L-Iduronidase in Mice With Mucopolysaccharidosis Type I,” Mol. Ther. 19:450-60 (2011)).
Pentosan polysulfate (PPS) is an FDA-approved, oral medication that has potent anti-inflammatory and clinical effects in animal models of several diseases, including lysosomal storage disorders, and more specifically MPS disorders (this application), as well as arthritis, diabetes, intervertebral disc degeneration, and age-related neurodegeneration. PPS is currently approved for use in patients with interstitial cystitis, and its safety has been demonstrated through clinical testing. PPS inhibits leukocyte recruitment and interferes with some functions of chemokines, cytokines, and growth factors, thereby reducing inflammation and reactive oxygen species (ROS).
Tumor necrosis factor alpha (TNF-α) is believed to play an important role in various disorders, including for example, inflammatory disorders such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, and multiple sclerosis. Both TNF-α and receptors CD120a, CD120b have been studied in great detail. TNF-α in its bioactive form is a trimer and the groove formed by neighboring subunits is important for the cytokine-receptor interaction. Several strategies to antagonize the action of the cytokine have been developed and are currently used to treat various disease states.
A TNF-α inhibitor which has sufficient specificity and selectivity to TNF-α may be an efficient prophylactic or therapeutic pharmaceutical compound for preventing or treating disorders where TNF-α has been implicated as a causative agent. Methods of treating toxic shock (EP Patent No. 0486526 to Rathjen et al.), tumor regression, inhibition of cytotoxicity (U.S. Pat. No. 6,448,380 to Rathjen et al., U.S. Pat. No. 6,451,983 to Rathjen et al., U.S. Pat. No. 6,498,237 to Rathjen et al.), autoimmune disease such as RA and Crohn's disease (EP Patent No. 0663836 to Feldmann et al., U.S. Pat. No. 5,672,347 to Aggarwal et al., U.S. Pat. No. 5,656,272 to Le et al.), graft versus host reaction (U.S. Pat. No. 5,672,347 to Aggarwal et al.), bacterial meningitis (EP Patent No. 0585705 to Hector et al.) by means of an antibody to TNF-α have been described. Previous work has also revealed the important impact of inflammation on the cartilage and bone disease in MPS animal models, and shown that genetic inhibition of Toll-like receptor 4 (TLR4) signaling in knockout mice or the use of TNF-inhibitors in combination with Naglazyme markedly improves cartilage and bone disease. Yet none of the presently available drugs are completely effective for the treatment of lysosomal storage disorders, particularly mucopolysaccharidosis and Niemann-Pick disease. TNF-inhibitors, while effective in the animal models, are intravenous medications that may result in significant side effects, and their long-term use in MPS patients may be difficult to implement.
The present invention is directed to overcoming these and other deficiencies in the art.